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Rationale High resolution computed tomography (HRCT) is a more sensitive tool for detecting early cystic fibrosis (CF) lung disease than either spirometry or plain radiography, but its relationship to other measures of lung function has not been established in young children. Objectives 1) To assess whether the lung clearance index (LCI) derived from multiple breath inert-gas washout (MBW) is as effective as HRCT in identifying pulmonary abnormalities; and 2) explore the relationships between abnormalities detected by HRCT and by spirometry, plethysmography and MBW (collectively, LFTs) in young children with CF. Methods Children with CF underwent LFTs and volumetric HRCT on the same day. Healthy age-matched controls underwent identical LFTs without HRCT. Scans were anonymised, and scored using the Brody-II CT scoring system, to assess for presence and extent of bronchiectasis, airway wall thickening, mucus plugging, and parenchymal opacities. Results Assessments were undertaken in 60 children with CF (mean (SD) 7.8 (1.3) years) and 54 healthy controls (7.9 (1.2) y). Among children with CF, 84% (47/56) had abnormal LCI, 58% (27/47) abnormal plethysmographic lung volumes (FRCpleth or RV), 35% (21/60) abnormal sRaw and 47% (28/60) abnormal spirometry (FEV1 or FEF25–75); whereas HRCT scans were abnormal in 85% (51/60): median total Brody-II score: 9.5% (range 0–51%). Total CT score correlated more strongly with LCI (Spearman correlation=0.77) than with spirometry (R=−0.43) or any other marker of lung function. Of the nine children with normal LCI, five had abnormalities on HRCT, whereas five children with normal HRCT had raised LCI. Conclusions These results suggest that while LCI and HRCT have similar sensitivity to detect CF lung disease, complimentary information may be gained in individual patients.

Background: Since January 2002, routine surveillance bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsy has been performed in all paediatric recipients of lung and heart–lung transplants at the Great Ormond Street Hospital for Children, London, UK, using a newly revised treatment protocol. Aims: To report the prevalence of rejection and bacterial, viral or fungal pathogens in asymptomatic children and compare this with the prevalence in children with symptoms. Participants: The study population included all paediatric patients undergoing single lung transplantation (SLTx), double lung transplantation (DLTx) or heart–lung transplantation between January 2002 and December 2005. Methods: Surveillance bronchoscopies were performed at 1 week, and 1, 3, 6 and 12 months after transplant. Bronchoscopies were classified according to whether subjects had symptoms, defined as the presence of cough, sputum production, dyspnoea, malaise, decrease in lung function or chest radiograph changes. Results: Results of biopsies and BAL were collected, and procedural complications recorded. 23 lung-transplant operations were performed, 12 DLTx, 10 heart–lung transplants and 1 SLTx (15 female patients). The median (range) age of patients was 14.0 (4.9–17.3) years. 17 patients had cystic fibrosis. 95 surveillance bronchoscopies were performed. Rejection (⩾A2) was diagnosed in 4% of biopsies of asymptomatic recipients, and in 12% of biopsies of recipients with symptoms. Potential pathogens were detected in 29% of asymptomatic patients and in 69% of patients with symptoms. The overall diagnostic yield was 35% for asymptomatic children, and 85% for children with symptoms (p Conclusions: Many children have silent rejection or subclinical infection in the first year after lung transplantation. Routine surveillance bronchoscopy allows detection and targeted treatment of these complications.

RATIONALE: Newborn screening (NBS) for cystic fibrosis (CF) allows early intervention. Design of randomised controlled trials (RCT) is currently impeded by uncertainty regarding evolution of lung function, an important trial end point in such infants.\ud \ud OBJECTIVE: To assess changes in pulmonary function during the first year of life in CF NBS infants.\ud \ud METHODS: Observational longitudinal study. CF NBS infants and healthy controls were recruited between 2009 and 2011. Lung Clearance Index (LCI), plethysmographic lung volume (plethysmographic functional residual capacity (FRCpleth)) and forced expired volume (FEV₀.₅) were measured at 3 months and 1 year of age.\ud \ud MAIN RESULTS: Paired measurements were obtained from 72 CF infants and 44 controls. At 3 months, CF infants had significantly worse lung function for all tests. FEV₀.₅ improved significantly (0.59 (95% CI 0.18 to 0.99) z-scores; p

Introduction Lung clearance index (LCI) is a sensitive measure of lung disease in infants, with potential applications in clinical practice and research. However, measuring LCI in infants is technically challenging and there is no simple method of assessing LCI outside of specialist research laboratories in this population. We have previously described an alternative method of measuring LCI, in which expired gas is collected and analysed to derive functional residual capacity (FRC) and LCI without directly measuring flow. This eliminates one of the major technical challenges, whilst also reducing the system’s dead space. This method is highly accurate in vitro, with a mean accuracy of FRC measurement to within 1%, down to FRC of 100ml.1 The method does not require large external gas tanks, and washout is performed breathing room air, making the system fully portable. Aim To assess the performance of this method in vivo. Method Healthy controls and infants with CF are currently being recruited to undergo LCI measurement using this method. Practical applicability of the system is determined by the number of successful tests and within-subject repeatability, defined as coefficient of variation (CV%) of same-visit repeats. Comparison will be made with LCI measurements obtained using a respiratory mass spectrometer, currently considered the gold standard for infant LCI measurement. Results To date, 10 healthy controls (mean age 53 weeks) and 2 infants with CF (mean age 55 weeks) have successfully undergone LCI measurement using this method. Mean LCI in controls was 6.62 (range 5.79–7.91). Mean within-subject CV% was 5.9%. Mean LCI in infants with CF was 7.63 (CV 5%). Conclusion Preliminary data suggest this is a feasible and reproducible method of performing LCI in infants. Results in both infants with CF and controls fall within ranges predicted by the respiratory mass spectrometer2 and within accuracy limits set by international guidelines. This could provide a more accessible alternative to current technologies, enabling this test to be offered in more centres. References Shawcross, et al. Ped Pulmonol 2016;51:491–497. Lum, et al. Eur Respir J 2013;41:1371–7.

Introduction Convection Dependent Inhomogeneity (CDI, a measure of ventilation inequality among larger lung units) quantified by Scond cannot be assessed in subjects with severe ventilation inhomogeneity (VI) as assumptions underlying the calculation are invalid; an alternate index that has been suggested is Scond.1 Aim To compare these two methods of CDI assessment in CF children Methods Children with cystic fibrosis (CF; 67) and healthy controls (61) performed multiple breath washout with sulphur hexaflouride measured using mass spectrometry. Scond was calculated from 1.5 to 6 turnovers and Scond* from breath 2 to 3 turnovers. Results All measures of VI were significantly higher for CF vs control, mean difference: LCI 4.0, Scond 0.054, Scond* 0.081. In CF, LCI correlated better with Scond* than Scond (See figure: correlation coefficient LCI vs. Scond* 0.75; LCI vs. Scond 0.42). If children with moderate-severe VI (LCI > 11) were excluded there was an improved correlation for both relationships (correlation coefficient LCI vs. Scond 0.83; LCI vs. Scond* 0.86). An asymptote for the Scond vs LCI relationship was at Scond 0.07 and Scond* 0.13. Conclusion Scond* quantifies the mechanism of VI in moderate to severe lung disease, but it may reach asymptote in very severe VI. Reference Verbanck. Respiratory Physiology & Neurobiology, 2013.

Background Breathing pattern cannot be controlled in small children, so multiple breath washout SnIII analysis has to exclude inadequate volume breaths. Aim To compare an existing mathematical breath exclusion algorithm with a physiological method. Methods School age children with CF (30) and controls (30) performed SF6MBW with mass spectrometer, with uncontrolled tidal breathing. Two different breath exclusion methods were compared, with exclusion based on: 1) Expired tidal volume (VT) deviating by >25% of the median VT1 2) VT Runs with >33% excluded breaths were removed. Volume corrected Scond was calculated from subjects with 3 valid runs. Results Far fewer subjects were excluded by the physiological Langley method, than by the mathematical method (Table). The mean and SD for Scond was identical by both methods, implying that the mathematical algorithm excludes valid data. Conclusion A physiological approach to data cleaning prior to SnIII analysis allows retention of data that would be inappropriately excluded mathematically. References Bigler A, et al. Paediatric Pulmonol 2015;50(8):805–13. Langley FE, et al. Colloques INSERM 1975;51:209–212.

Assessment of ventilation inhomogeneity using the multiple breath washout (MBW) technique has been shown to be more sensitive than spirometry in detecting early cystic fibrosis lung disease throughout childhood. The current “gold standard” interface for school age children and adults is a mouthpiece. Although masks are better tolerated by infants and younger children, their use increases equipment deadspace-which could influence measured values and hence interpretation of results. The aim of this study was to examine the effect of using a mask vs mouthpiece on values of functional residual capacity (FRC) and the lung clearance index (LCI) derived from MBW. Method Comparisons were performed in healthy adults. The study design incorporated repeated measures as well as interface comparison. The mask was selected to mimic measurement conditions in infants, the deadspace of 85 mL being approximately 1–2 ml/kg in adults. Mouthpiece (MP) deadspace was ~5 ml. Subjects were randomly allocated to group A (Mask-Mouthpiece-Mouthpiece) or group B (Mouthpiece-Mouthpiece-Mask) protocols. Each subject performed a total of 9 MBW runs, in 3 sets, each consisting of 3 runs, with a 5-minute break between each set. MBW was performed using a mass spectrometer as described previously (Aurora 2005 AJRCCM). Paired t-tests with 95% limits of agreement were used to establish repeatability (MP1 vs. MP2) and any differences between Mask vs. Mouthpiece. This study was approved by the local research ethics committee and written consent obtained from subjects. Results Technically satisfactory comparative data were obtained on 15 occasions in 14 adults (36% males; age: 22–56 years). Respiratory rate and tidal volume were similar using either approach. Repeatability: Both FRC and LCI were repeatable using the mouthpiece [(Mean (95% CI) diff: FRC: 0.012L (-0.05;0.07); LCI: -0.1(-0.3; 0.1)]; Figure 1A and B. Mask vs. Mouthpiece: FRC and LCI were both significantly higher when assessments were made using a mask compared with a mouthpiece: FRC: 0.101L (0; 0.202); LCI: 0.4 (0.2;0.7); Figure 1C and D. Conclusion The increase in LCI when using a facemask exceeded normal within test variability in adults and could influence interpretation of results especially if different patient interfaces are used when collecting data in younger children.

Background Lung clearance index (LCI) measured by multiple breath washout (MBW) is a sensitive indicator of early lung disease in Cystic Fibrosis (CF). 1 MBW using sulphur hexafluoride (SF 6 ) and mass spectrometry (MS) is currently the gold standard, but equipment is limited to a few centres. Although commercial devices based on SF 6 have been developed, use of SF 6 is expensive and restricted in some countries. Commercial devices using nitrogen (N 2 ), which is cheaper and widely available, have been developed recently to increase accessibility of this test in research and clinical practice but have yet to be validated in children. The aim of this study was to compare values of LCI and Functional Residual Capacity (FRC) in children using the N 2- MBW EasyOne Pro® LAB system (ndd Medical Technologies) and the MS (AMIS 2000, Innovision ApS). Methods School-age children with CF and healthy controls completed MBW in triplicate on both the EasyOne Pro® and MS in random order on the same occasion. Within-subject agreement between devices for LCI and FRC was assessed by Bland-Altman analysis. Results Of the 50 children recruited, all completed testing using MS, while 5 failed quality control on the EasyOne Pro® LAB. Paired results from both devices were obtained in 26 children with CF (mean age [range]) (13.3y[7.8y-17.4y]) and 19 controls (14.8y [12.5y-16.7y]). LCI was significantly higher in those with CF when using both devices (mean difference[95% CI], CF-controls): 2.47[1.4;3.5] for the MS-SF 6 and 2.20[1.2–3.2] for N 2 -MBW. There were no significant group differences between devices for either LCI (mean difference[95% CI]) -0.14[-0.45;0.16] or FRC -0.15L[-0.2;-0.08]. Within-subject variability was proportional to mean values (see Figure) and ranged from 0.4–15.7% for LCI and 0.0–19.6% for FRC. Conclusion Despite some previous reports that N 2- washout results in higher LCI values than MS-SF 6 washout, on average, we found similar values in both healthy school-age children and those with CF. Further work is required to examine causes of within-subject variability and assess validity and sensitivity over a wider age range, including preschool children, before commercial N 2 -MBW devices can be confidently used in multi-centre trials. Reference Aurora et al . Am J Respir Crit Care Med. 2011;183:752–8

Background In patients with cystic fibrosis (CF), interpretation of cross-sectional FEV1 data is greatly influenced by choice of spirometry reference equation, particularly during childhood (Stanojevic; J Cyst Fibros 2014). We hypothesised that availability of the Global Lung Function Initiative (GLI) spirometry reference equations (Quanjer; ERJ 2012) will also affect the apparent rate of decline in lung function over time, thereby potentially altering our understanding of disease progression in CF. Methods Data were extracted from two patient registries: the UK CF Registry (n = 6043 subjects; 20,013 test occasions over a period of 5 years) and the Toronto CF database (n = 1023 subjects; 27,868 test occasions over a period of 23 years). Spirometric outcomes were interpreted using%predicted FEV1 calculated from GLI, Knudson (as currently used by the UK CF Registry), and Wang-Hankinson (as used by the US CF Foundation) reference equations. Patients >30 yrs or with FEV1 > 130% predicted were excluded. We used a non-linear mixed effects model to describe the average change in FEV1 with age. To illustrate the importance of reference equation in evaluating risk factors, FEV1 decline according to patient gender was also explored. Results The pattern of lung function decline at the population level differed according to selected equation (Figure). Average rate of decline was steeper with Knudson or Wang-Hankinson than GLI. Importantly, GLI equations showed a steady decline in FEV1 starting at 6 yrs, whereas the other equations suggest greater decline during adolescence. Similar patterns were observed in both UK and Toronto populations. When analysed according to gender, the rate of lung function decline was steeper in females during early adolescence compared with males where the decline was steady. Conclusions In both datasets, Knudson and Wang-Hankinson reference equations suggest relative preservation of spirometry in childhood followed by rapid decline in adolescence. However using the more robust GLI equations, steady decline throughout childhood with a less dramatic acceleration during adolescence is seen, with differences in pattern of change over time according to patient gender. Accurate identification of critical periods of lung function decline offers novel opportunities to target care. Funded by the UK CF Trust.

Background Multiple breath inert-gas washout (MBW) using sulphur hexafluoride (SF 6 ) measured by mass spectrometry (MS), is sensitive to early lung disease in children with Cystic Fibrosis (CF) 1 but is not widely available. To increase the accessibility of MBW, commercial devices have been adapted using nitrogenwashout (N 2 -MBW). Our aim was to assess the feasibility of two commercial N 2 -MBW devices as supplied by the manufacturers compared to a custom-built MS system in school-aged children. Methods Patients with CF and controls performed MBW on three devices; the Exhalyzer ® D (ECO MEDICS AG); the EasyOne Pro ® LAB (ndd Medizintechnik AG) and the MS system (AMIS 2000, Innovision ApS) on the same test occasion (order randomised). Attempts were made to obtain 3 technically acceptable runs/device (maximum 8 attempts on each). During testing children watched a DVD and were encouraged to breathe normally. Data were analysed using the ‘clinical application’ setting for both commercial devices, and customised software for the MS. Quality control was in accordance with the ATS/ERS consensus statement 1 and manufacturers’ guidelines. Results 14 control (mean[range]age: 15.0[12.5–16.7]yrs) and 18 children with CF (13.5[7.8–17.4]yrs) were assessed. The median (range) number of runs attempted were: MS 3(3–8), Exhalyzer ® D 4(3–6), EasyOne Pro ® LAB 4(3–8). Average calibration time was shorter for EasyOne Pro ® LAB (5 min) than either MS (11 mins) or Exhalyzer ® D (12 min). Total test duration was similar between devices and dependent on disease severity. 3 acceptable MBW runs were achieved in all children using the MS, 75% with the EasyOne Pro ® LAB, and 47% on the Exhalyzer ® D system (see Table). Reasons for failure with Exhalyzer ® D were usually due to technical/equipment problems, whereas for the EasyOne Pro ® LAB these were generally associated with marked changes of breathing pattern at commencement of washout, leading to exclusion of one or more runs. Discussion Despite use in an experienced MBW centre, our initial attempts to implement commercial MBW devices according to manufacturers’ guidelines resulted in a relatively low success rate in schoolchildren when compared to MS. Subsequent feedback to manufacturers has led to further adaptations which should improve feasibility in future, although this has yet to be assessed in very young children. Reference Robinson et al . Eur Resp J 2013